title: Discovery of novel bacterial RNA polymerase inhibitors: pharmacophore-based virtual screening and hit optimization.
abstract: The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ(70) and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, and ‡Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinsberger
authors.forename: Kristina
authors.initials: K
authors.lastname: Hüsecken
authors.forename: Matthias
authors.initials: M
authors.lastname: Groh
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Jörg
authors.initials: J
authors.lastname: Haupenthal
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012321:DNA-Directed RNA Polymerases